To date more than 10 genes are known to be associated with familial paraganglioma/phaeochromocytoma (including RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127 and MAX). It is likely that more will be identified.

Genetic testing is essential for good clinical care of individuals who are suspected of having a heritable mutation predisposing to phaeochromocytoma or paraganglioma.

assessment for clinical features of von Hippel-Lindau (VHL); features including personal or family history of CNS or retinal haemangioblastomas and clear cell renal cancer (Genetic testing for heritable mutations in the VHL gene and link to VHL diagnostic criteria when available)r

assessment for clinical features of multiple endocrine neoplasia type 2 (MEN2); features include personal or family history of medullary thyroid cancer and/or primary hyperparathyroidism (consider MEN2 link to RET mutation testing criteria when available).

Immunohistochemical studies:

SDHB and SDHA immunohistochemistry (SDHB-IHC and SDHA-IHC) is indicated on both apparently sporadic and familial cases of paraganglioma or phaeochromocytomarr

abnormal (absent) SDHB-IHC has >99% sensitivity, and 84% specificity for mutations in SDHB, SDHC and SDHDr

SDHB-IHC is also abnormal in SDHA associated paraganglioma/phaeochromocytoma, although the sensitivity and specificity has not been definedr

the limited available data suggests SDHA-IHC is abnormal in SDHA associated paraganglioma/phaeochromocytoma but normal in tumours associated with mutations in other SDH subunit genesr

the role of SDHB-IHC and/or SDHA-IHC for mutations in SDHAF2 is unknown.

there is evidence that the pattern of plasma metanephrine, normetanephrine and 3-methoxytyramine secretion varies with the gene involved.r When panel testing of multiple genes is not available this may be useful for prioritising the order in which to test the currently known paraganglioma-phaeochromocytoma genes Genetic testing algorithm for paraganglioma-phaeochromocytoma.

Approximately one third of unselected individuals with phaeochromocytoma and/or paraganglioma have a germline mutation in one of the 6 main genes (VHL, RET, NF1, SDHB, SDHD and SDHC). Mutations are identified in 11-18% of individuals with apparently sporadic presentation and 40-70% with a family history.

Germline mutations in SDHAF2, TMEM127, MAX and SDHA have been reported in both apparently sporadic and familial phaeochromocytoma and/or paraganglioma. The prevalence of mutations in these genes is low, but poorly defined.rr

Patient has a first or second degree relative with documented pathogenic mutation

25-50%

Dutch ancestry

89% of all SDH mutations are due to 6 founder mutations

#In this section of the table the >symbol is utilised to represent more likely than
*Reported series are all clinic based and are affected by specific effects of ascertainment. Population based estimates are not currently available.
**Excludes unilateral adrenal phaeochromocytoma
***Includes bilateral adrenal phaeochromocytoma

Note: It is often difficult to compare mutation pick up by clinical phenotype across different study cohorts; some studies excluded patients with syndromic features of VHL, NF1 or MEN2 others did not; some excluded a family history of paraganglioma whilst others did not; some used the WHO classification for paraganglioma/phaeochromocytoma, others did not.

For further references used to develop this table please see the History icon.

Further references

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au